The overall goal of this research is to develop novel DNA-modulated drug release nanoparticles (DDRNP) that can target and treat melanoma, or other type of cancer, with high specificity. Nanotechnology is an emerging field that has shown promise for the development of novel diagnostic, imaging and therapeutic agents for a variety of diseases, including cancer. One major obstacle to the effective clinical application of nano-therapeutic or nano-imaging agents is the lack of high affinity and high specificity targeting ligands that can deliver these nanomedicines to the tumor or organ target site with high efficiency in vivo. There are presently needs for alternative methods of delivery and targeting for future nanomedicines. We have recently reported (Peng, 2006) the identification of a high-affinity (IC50=2 pM) peptidomimetic ligand (LLP2A) against activated 1421 integrin using both diverse and highly focused one-bead one-compound (OBOC) combinatorial peptidomimetic libraries in conjunction with a high stringency screening method. We further demonstrated that LLP2A is able to image 1421- expressing lymphomas with high sensitivity and specificity when conjugated to a near infrared fluorescent dye in a murine xenograft model. In addition, it also binds to the growing blood vessels of many tumor types. We have also reported the identification of an ovarian cancer targeting ligand (OA02) that bind to 1321 integrin with high specificity (Aina, 2005a). In vivo optical (Aina, 2005b) and PET (Aina, 2007) imaging studies have confirmed its cancer targeting potential. Very recently, we were able to demonstrate that this and related ligands can target malignant melanoma with high specificity (see Preliminary Data section). Anthracyclines are a class of potent DNA intercalating drugs used for treatment of cancer, including melanoma, but their therapeutic efficacy is limited by their toxicity and lack of specificity. We are envisaging that their efficient dsDNA intercalation can be exploited to develop a new drug delivery paradigm by creating short anthracycline-laden dsDNA sequences as drug carriers whereby their thermal denaturation triggers the localized release of the anticancer drug. Magnetic nanoparticles (MNPs) carrying both anthracycline-loaded dsDNA sequences and OA02/LLP2A targeting ligands will be delivered selectively to cancer tissues. An external high frequency electromagnetic field (radiofrequency or RF heating) will be transduced by the MNP to a localized thermal output causing dsDNA denaturation and concomitant in situ drug release. Our hypothesis is that the DNA-modulated drug release concept applied in conjunction to melanoma targeting ligands, will be useful as adjuvant therapy for stage I, II, and III melanoma patients, and as palliative therapy for patients with more advanced disease. In this R21 application we shall develop this novel nanotherapeutic approach in a melanoma xenograft model. The specific aims of this application are as follows: Aim 1: To develop, prepare, and characterize DNA-modulated drug release nanoparticles (DDRNP) decorated with OA02 (a melanoma targeting ligand), and/or LLP2A (a tumor blood vessel targeting ligand). Aim 2: To evaluate the RF triggered in vitro release and anti-cancer effects of doxorubicin (DOX) from DDRNP. Aim 3: To evaluate the biodistribution and intratumoral distribution of DDRNPs in the murine xenograft model for melanoma. Title: DNA-modulated release of drug from melanoma targeting NP Project Narrative Short anthracycline-laden dsDNA sequences can be used as drug carriers whereby their thermal denaturation triggers the localized release of the anticancer drug. Magnetic nanoparticles (MNPs) carrying both anthracycline-loaded dsDNA sequences and OA02/LLP2A targeting ligands will be delivered selectively to cancer tissues. An external high frequency electromagnetic field (radiofrequency or RF heating) will be transduced by the MNP to a localized thermal output causing dsDNA denaturation and concomitant in situ drug release. Our hypothesis is that the DNA-modulated drug release concept applied in conjunction to melanoma targeting ligands, will be useful as adjuvant therapy for stage I, II, and III melanoma patients, and as palliative therapy for patients with more advanced disease. In this R21 application we shall develop this novel nanotherapeutic approach in a melanoma xenograft model.